Nature communicationsNov 20, 2025

How Psilocybin Affects Opioid Addiction Differently in Males and Females

Psychedelic Science Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jan 1, 2026

Abstract

A single administration of psilocybin reduces conditioned behavior and withdrawal from oxycodone in male mice.

Psychedelics may have therapeutic potential for opioid use disorder by addressing altered reward processing and dependence.
The effects of psilocybin on reducing oxycodone preference are mediated through the activation of the 5-HT receptor in specific brain neurons.
Sex differences are observed, with psilocybin's effects on oxycodone preference present in males but not in females.
Psilocybin influences epigenomic regulation after repeated oxycodone exposure, leading to changes in brain structure.
Female mice show fewer epigenomic changes in response to psilocybin and oxycodone compared to males, particularly in the frontal cortex.

Simplified

Emerging evidence suggests that classical psychedelics may offer therapeutic potential for opioid use disorder (OUD) by alleviating key hallmarks such as altered reward processing and dependence. However, the mechanisms behind these effects remain unclear. Our data demonstrate that a single administration of the psychedelic psilocybin (PSI) reduces conditioned behavior and withdrawal induced by the opioid oxycodone (OXY) in male mice but not in females, and this effect is mediated via the 5-HTreceptor (5-HTR). We show that the sex-specific attenuation of OXY preference is driven by 5-HTR activation in frontal cortex pyramidal neurons projecting to the nucleus accumbens (NAc). Additionally, PSI modulates epigenomic regulation following repeated OXY exposure and induces sex-specific NAc dendritic structural plasticity independently of 5-HTR. Notably, female frontal cortex and NAc show fewer changes at gene enhancer regions in response to PSI, repeated OXY, or combined PSI-OXY treatment compared to males, with the frontal cortex exhibiting more pronounced sex differences than the NAc at the epigenomic level. Together, these results provide new insights into the neural and epigenetic mechanisms of psychedelic-induced plasticity in OUD, while also highlighting sex differences in PSI's modulation of reward pathways and its therapeutic potential. 2A2A2A2A

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How Psilocybin Affects Opioid Addiction Differently in Males and Females

Abstract

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